A recent study published in Nature Communications investigates the impact of DAV132, a colon-targeted adsorbent, on the plasma concentrations of several key beta-lactam antibiotics and explores its effects on the gut microbiome. The randomized, open-label, controlled trial (CL-006) found that DAV132 did not significantly interfere with the plasma concentrations of ceftriaxone, piperacillin, tazobactam, ceftazidime, and avibactam in healthy volunteers. However, exploratory analyses revealed potential protective effects of DAV132 on the intestinal microbiome during antibiotic treatment, as well as potential to enhance anti-PD-1 immunotherapy in mice.
The study, conducted between May and December 2019, enrolled 148 healthy volunteers who were randomized to receive either DAV132 (7.5g or 12g three times daily for 7 days) in combination with antibiotics (ceftriaxone, piperacillin/tazobactam, or ceftazidime/avibactam) or antibiotics alone. The primary objective was to assess the effect of DAV132 on the plasma concentration of beta-lactams at steady-state. Secondary objectives included safety assessments and potential interactions of DAV132 on fecal excretion of beta-lactams. Exploratory objectives focused on the protective effect of DAV132 on intestinal microbiome diversity.
Impact on Antibiotic Plasma Concentrations
The primary endpoint of the study was to determine if DAV132 altered the AUC0-τ of piperacillin, tazobactam, ceftazidime, avibactam, and ceftriaxone plasma levels. The results indicated that DAV132, at either dose, did not significantly affect the plasma concentrations of these antibiotics. This suggests that DAV132 can be co-administered with these antibiotics without compromising their systemic exposure.
Effects on Gut Microbiome Diversity
Exploratory analyses using 16S rRNA gene sequencing and metagenomics revealed that DAV132 may have a protective effect on the intestinal microbiome during antibiotic treatment. The study assessed the impact of DAV132 on the gut microbiome diversity using the Shannon index and Bray-Curtis dissimilarity index. While the primary focus was not statistical significance, the data suggested a trend toward preserved microbial diversity in the DAV132 groups compared to those receiving antibiotics alone. These findings suggest a potential role for DAV132 in mitigating antibiotic-associated dysbiosis.
DAV132 and Anti-PD-1 Immunotherapy
To investigate the potential of DAV132 to enhance the efficacy of anti-PD-1 immunotherapy, researchers conducted experiments in mice bearing MCA-205 fibrosarcoma or B16-OVA melanoma tumors. Fecal microbiota transplantation (FMT) was performed using fecal material from healthy volunteers enrolled in the DAV132 clinical trial. The results showed that FMT from DAV132-treated individuals enhanced the response to anti-PD-1 therapy in mice. Specifically, mice receiving FMT from DAV132-treated donors exhibited reduced tumor growth and increased infiltration of CD8+ T cells into the tumor microenvironment. These findings suggest that DAV132 may modulate the gut microbiota in a way that enhances the anti-tumor immune response.
Implications for Clinical Practice
While the primary finding of this study is that DAV132 does not interfere with the plasma concentrations of key beta-lactam antibiotics, the exploratory analyses suggest potential benefits for gut microbiome protection and enhancement of anti-PD-1 immunotherapy. Further research is warranted to fully elucidate the mechanisms underlying these effects and to determine the clinical significance of DAV132 in these contexts. The study highlights the complex interplay between antibiotics, the gut microbiome, and the immune system, and suggests that targeted interventions like DAV132 may offer a promising strategy to optimize antibiotic therapy and improve cancer immunotherapy outcomes.
